N-methylated peptides have attracted considerable attention from chemists because of their improved cell permeability and stability relative to peptides and their appearance in a host of bioactive natural products. At the other end of the spectrum are peptoids, in which diverse groups are appended to the main chain nitrogen, but the amino acid unit is always glycine (Simon, et al., Proc. Natl. Acad. Sci. USA 1992, 89, 9367-71).
N-methylated peptides, however, are restricted to only a methyl substituent on the nitrogen atom, and thus, are impractical for the creation of large, diverse combinatorial libraries.
One bead one compound (OBOC) libraries of peptoids (oligo-N-substituted glycines) have been shown to be an excellent source of selective protein ligands. Peptoids are almost ideal molecules for library construction via split and pool synthesis since they are synthesized via a protocol that allows cheap, readily available primary amines to be employed as diversity elements. Moreover, peptoid structures can be deduced readily by tandem mass spectrometry, eliminating the need for library encoding. Finally, the absence of the highly polar and well-hydrated backbone N—H bonds renders peptoids far more cell permeable than peptides, which is important for targeting intracellular proteins. However, there have been few reports of high affinity peptoid-protein interactions with KD values in the low nM range, which is highly desirable in a drug lead or in a tool compound. Without being bound by any theory, it is likely that this is due, at least in part, to the inherent “floppiness” of peptoids. In most cases, the cis and trans amide bond isomers are close to one another in energy and so peptoids exist as a complicated mixture of these conformational isomers. Moreover, there is little obstruction in rotation about both the carbonyl-Cα and the Cα-nitrogen bonds. Assuming that protein-binding peptoids assume a particular conformation upon binding to their target, this means that a large entropic penalty must be paid, which will limit affinity. Several laboratories have reported approaches to controlling the amide bond geometry in peptoids, but these approaches are not readily applicable to the synthesis of large, high-quality combinatorial libraries. These approaches do not significantly address the issue of restricting rotation about the carbonyl-Cα and the Cα-nitrogen bonds.